Quinuclidine derivatives as substance P antagonists

Abstract

PCT No. PCT/US93/01810 Sec. 371 Date Oct. 3, 1994 Sec. 102(e) Date Oct. 3, 1994 PCT Filed Mar. 5, 1993 PCT Pub. No. WO93/19064 PCT Pub. Date Sep. 30, 1993Compounds useful in the treatment of inflammatory disorders, central nervous system disorders and other disorders of formula (I) and the pharmaceutically-acceptable salts thereof, wherein X1 is alkoxy or halosubstituted alkoxy; X2 is hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halosubstitued alkyl, halosubstituted alkoxy, alkylamino, dialkylamino, alkylsulfonylamino (which may be substituted), N-alkyl-N-alkylsulfonylamino (which may be substituted), alkanoylamino (which may be substituted) or N-alkyl-N-alkanoylamino (which may be substituted); Ar1 and Ar2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl; A is Y-(CH2)m-CH(R2)-(CH2)n-NR1-; R1 is hydrogen, alkyl, benzyl or -(CH2)p-Y; R2 is hydrogen, alkyl (which may be substituted), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or -(CH2)p-Y; Y is -CN, -CH2Z or -COZ; Z is hydroxy, amino, alkoxy, alkylamino or dialkylamino; m, n and p are each, independently, 0, 1, 2 or 3; and R1 and R2 may be connected to form a ring.

We claim: 
     
       1. A compound of the following chemical formula ##STR5## and the pharmaceutically-acceptable salts thereof, wherein X 1  is C 1  -C 5  alkoxy or halosubstituted (C 1  -C 5 ) alkoxy; X 2  is hydrogen, halogen, C 1  -C 5  alkyl, C 2  -C 5  alkenyl, C 2  -C 5  alkynyl, C 1  -C 5  alkoxy, C 1  -C 5  alkylthio, C 1  -C 5  alkylsulfinyl, C 1  -C 5  alkylsulfonyl, halosubstituted (C 1  -C 5 ) alkyl, halosubstituted (C 1  -C 5 ) alkoxy, C 1  -C 5  alkylamino, dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety, C 1  -C 5  alkylsulfonylamino (which may be substituted by halogen), N-(C 1  -C 5 )alkyl-N-(C 1  -C 5 )alkylsulfonylamino (which may be substituted by halogen in the alkylsulfonyl moiety), C 1  -C 5  alkanoylamino (which may be substituted by halogen) or N-(C 1  -C 5 )alkyl-N-(C 1  -C 5 )alkanoylamino (which may be substituted by halogen in the alkanoyl moiety);   Ar 1  and Ar 2  are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;   A is Y--(CH 2 ) m  --CH(R 2 )--(CH 2 ) n  --NR 1  --;   R 1  is hydrogen, C 1  -C 5  alkyl, benzyl or --(CH 2 ) p  --Y;   R 2  is hydrogen, C 1  -C 5  alkyl (which may be substituted by the substituent which is selected from the group consisting of hydroxy, amino, methylthio and mercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or --(CH 2 ) p  --Y;   Y is --CN, --CH 2  Z or --COZ;   Z is hydroxy, amino, C 1  -C 5  alkoxy, C 1  -C 5  alkylamino or dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety;   m, n and p are each, independently, 0, 1, 2 or 3; and   R 1  and R 2  may be connected to form a ring.   
     
     
       2. A compound according to claim 1, wherein X 1  is 2-methoxy and Ar 1  and Ar 2  are each phenyl. 
     
     
       3. A compound according to claim 2, wherein X 2  is selected from the group consisting of ethyl, n-propyl, isopropyl, t-butyl, isopropenyl, methylthio, methylsulfinyl, methylsulfonyl, trifluoromethoxy, dimethylamino, N-methyl-N-methylsulfonylamino and N-methyl-N-acetylamino. 
     
     
       4. A compound according to claim 3, wherein Y is --CONH 2  or --COOH. 
     
     
       5. A compound according to claim 4, wherein R 1  is hydrogen. 
     
     
       6. A compound according to claim 5, wherein m is 0, n is 0 or 1 and R 2  is hydrogen, methyl, benzyl or isobutyl. 
     
     
       7. A compound according to claim 3, wherein R 1  and R 2  together with --CH--(CH 2 ) n  --N-- form a five membered ring, n is zero, m is zero, Y is --COZ, and Z is hydroxy, amino, C 1  -C 5  alkylamino or C 1  -C 5  dialkylamino. 
     
     
       8. A compound according to claim 2, in which the configuration is (3R*,4S,5S,6S) or (2S*,4S,5S,6S). 
     
     
       9. A compound according to claim 1, which is selected from the group consisting of: (3R,4S,5S,6S)-N-Carbamoylmethyl-5-(5-isopropyl-2-methoxybenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N-Carboxymethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-3-(2-Carbamoylpyrrolidin-1-yl)carbonyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane;   (3R,4S,5S,6S)-N-(1-Carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N-(1-Carbamoyl-3-methylbutyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N-(2-Carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N-(1-Carbamoyl-2-phenylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N,N-bis(Cyanomethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N-carbamoylmethyl-5-(5-t-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N-carbamoylmethyl-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N-carbamoylmethyl-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N-carbamoylmethyl-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;   (3R,4S,5S,6S)-N-carbamoylmethyl-5-(2-methoxy-5-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide; and   (3R,4S,5S,6S)-N-carbamoylmethyl-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide.   
     
     
       10. A compound according to claim 9, which is (3R,4S,5S,6S)-N-Carbamoylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide. 
     
     
       11. A substance P antagonist which comprises a therapeutically effective amount of a compound of claim 1 or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier. 
     
     
       12. A method of antagonizing substance P in a mammalian subject in need of such treatment which comprises administering to said mammalian subject an effective amount of a compound according to claim 1. 
     
     
       13. A pharmaceutical composition for the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, asthma, pain or migraine which comprises a therapeutically effective amount of a compound of claim 1 or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier. 
     
     
       14. A method of treating gastrointestinal disorders, central nervous system disorders, inflammatory diseases, asthma, pain or migraine in a mammalian subject in need of such treatment which comprises administering to said mammalian subject an effective amount of a compound according to claim 1.